Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor.

LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)1, a New World alphavirus that causes severe neurological disease in humans. Here we present near-atomic-resolution cryo-electron microscopy reconstructions of VEEV virus-like particles alone and in a complex with the ectodomains of LDLRAD3. Domain 1 of LDLRAD3 is a low-density lipoprotein receptor type-A module that binds to VEEV by wedging into a cleft created by two adjacent E2-E1 heterodimers in one trimeric spike, and engages domains A and B of E2 and the fusion loop in E1. Atomic modelling of this interface is supported by mutagenesis and anti-VEEV antibody binding competition assays. Notably, VEEV engages LDLRAD3 in a manner that is similar to the way that arthritogenic alphaviruses bind to the structurally unrelated MXRA8 receptor, but with a much smaller interface. These studies further elucidate the structural basis of alphavirus-receptor interactions, which could inform the development of therapies to mitigate infection and disease against multiple members of this family.

LDLRAD3 is a receptor for Venezuelan equine encephalitis virus.

Venezuelan equine encephalitis virus (VEEV) is a neurotropic alphavirus transmitted by mosquitoes that causes encephalitis and death in humans1. VEEV is a biodefence concern because of its potential for aerosol spread and the current lack of sufficient countermeasures. The host factors that are required for VEEV entry and infection remain poorly characterized. Here, using a genome-wide CRISPR-Cas9-based screen, we identify low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3)-a highly conserved yet poorly characterized member of the scavenger receptor superfamily-as a receptor for VEEV. Gene editing of mouse Ldlrad3 or human LDLRAD3 results in markedly reduced viral infection of neuronal cells, which is restored upon complementation with LDLRAD3. LDLRAD3 binds directly to VEEV particles and enhances virus attachment and internalization into host cells. Genetic studies indicate that domain 1 of LDLRAD3 (LDLRAD3(D1)) is necessary and sufficient to support infection by VEEV, and both anti-LDLRAD3 antibodies and an LDLRAD3(D1)-Fc fusion protein block VEEV infection in cell culture. The pathogenesis of VEEV infection is abrogated in mice with deletions in Ldlrad3, and administration of LDLRAD3(D1)-Fc abolishes disease caused by several subtypes of VEEV, including highly virulent strains. The development of a decoy-receptor fusion protein suggests a strategy for the prevention of severe VEEV infection and associated disease in humans.

Logistic regression analysis of clinical and computed tomography features of pulmonary abscesses and risk factors for pulmonary abscess-related empyema.

OBJECTIVES: This study was conducted to investigate the risk factors for pulmonary abscess-related empyema by investigating the clinical characteristics and chest computed tomography imaging features of patients with pulmonary abscesses. METHODS: We retrospectively analyzed the chest computed tomography findings and clinical features of 101 cases of pulmonary abscess, including 25 cases with empyema (the experimental group) and 76 cases with no empyema (the control group). The potential risk factors for pulmonary abscess-related empyema were compared between the groups by using univariate and multivariate logistic regression analyses. RESULTS: The incidence of pulmonary abscess-related empyema was 24.8% (25/101). Univariate analysis showed that male gender, diabetes, pleuritic symptoms, white blood cells >10×109/L, albumin level <25 g/L, and positive sputum cultures were potential clinical-related risk factors and that an abscess >5 cm in diameter and transpulmonary fissure abscesses were potential computed tomography imaging-related risk factors for pulmonary abscess-related empyema. Multivariate logistic regression analysis showed that transpulmonary fissure abscesses (odds ratio=9.102, p=0.003), diabetes (odds ratio=9.066, p=0.003), an abscess >5 cm in diameter (odds ratio=8.998, p=0.002), and pleuritic symptoms (odds ratio=5.395, p=0.015) were independent risk factors for pulmonary abscess-related empyema. CONCLUSIONS: Transpulmonary fissure abscesses, diabetes, giant pulmonary abscesses, and pleuritic symptoms increased the risk of empyema among patients with pulmonary abscesses.

Logistic regression analysis of clinical and computed tomography features of pulmonary abscesses and risk factors for pulmonary abscess-related empyema

OBJECTIVES: This study was conducted to investigate the risk factors for pulmonary abscess-related empyema by investigating the clinical characteristics and chest computed tomography imaging features of patients with pulmonary abscesses. METHODS: We retrospectively analyzed the chest computed tomography findings and clinical features of 101 cases of pulmonary abscess, including 25 cases with empyema (the experimental group) and 76 cases with no empyema (the control group). The potential risk factors for pulmonary abscess-related empyema were compared between the groups by using univariate and multivariate logistic regression analyses. RESULTS: The incidence of pulmonary abscess-related empyema was 24.8% (25/101). Univariate analysis showed that male gender, diabetes, pleuritic symptoms, white blood cells >10×109/L, albumin level <25 g/L, and positive sputum cultures were potential clinical-related risk factors and that an abscess >5 cm in diameter and transpulmonary fissure abscesses were potential computed tomography imaging-related risk factors for pulmonary abscess-related empyema. Multivariate logistic regression analysis showed that transpulmonary fissure abscesses (odds ratio=9.102, p=0.003), diabetes (odds ratio=9.066, p=0.003), an abscess >5 cm in diameter (odds ratio=8.998, p=0.002), and pleuritic symptoms (odds ratio=5.395, p=0.015) were independent risk factors for pulmonary abscess-related empyema. CONCLUSIONS: Transpulmonary fissure abscesses, diabetes, giant pulmonary abscesses, and pleuritic symptoms increased the risk of empyema among patients with pulmonary abscesses.